190589-71-0Relevant academic research and scientific papers
A Guanidyl-Based Bivalent Peptidomimetic Inhibits K-Ras Prenylation and Association with c-Raf
Tsubamoto, Mai,Le, Toan Khanh,Li, Minghua,Watanabe, Taku,Matsumi, Chiemi,Parvatkar, Prakash,Fujii, Hiroshi,Kato, Nobuo,Sun, Jiazhi,Ohkanda, Junko
, p. 13531 - 13536 (2019/10/28)
Unusual lipid modification of K-Ras makes Ras-directed cancer therapy a challenging task. Aiming to disrupt electrostatic-driven protein–protein interactions (PPIs) of K-Ras with FTase and GGTase I, a series of bivalent dual inhibitors that recognize the active pocket and the common acidic surface of FTase and GGTase I were designed. The structure-activity-relationship study resulted in 8 b, in which a biphenyl-based peptidomimetic FTI-277 was attached to a guanidyl-containing gallate moiety through an alkyl linker. Cell-based evaluation demonstrated that 8 b exhibited substantial inhibition of K-Ras processing without apparent interference with Rap-1A processing. Fluorescent imaging showed that 8 b disrupts localization of K-Ras to the plasma membrane and impairs interaction with c-Raf, whereas only FTI-277 was found to be inactive. These results suggest that targeting the PPI interface of K-Ras may provide an alternative method of inhibiting K-Ras.
Module assembly for protein-surface recognition: Geranylgeranyltransferase I bivalent inhibitors for simultaneous targeting of interior and exterior protein surfaces
Machida, Shinnosuke,Usuba, Kakeru,Blaskovich, Michelle A.,Yano, Akiko,Harada, Kazuo,Sebti, Said M.,Kato, Nobuo,Ohkanda, Junko
supporting information; experimental part, p. 1392 - 1401 (2009/04/07)
Synthetic chemical probes designed to simultaneously targeting multiple sites of protein surfaces are of interest owing to their potential application as site specific modulators of protein-protein interactions. A new approach toward bivalent inhibitors of mammalian type I geranylgeranyltransferase (GGTase I) based on module assembly for simultaneous recognition of both interior and exterior protein surfaces is reported. The inhibitors synthesized in this study consist of two modules linked by an alkyl spacer; one is the tetrapeptide CVIL module for binding to the interior protein surface (active pocket) and the other is a 3,4,5-alkoxy substituted benzoyl motif that contains three aminoalkyl groups designed to bind to the negatively charged protein exterior surface near the active site. The compounds were screened by two distinct enzyme inhibition assays based on fluorescence spectroscopy and incorporation of a [ 3H]-labeled prenyl group onto a protein substrate. The bivalent inhibitors block GGTase I enzymatic activity with Ki values in the submicromolar range and are approximately one order of magnitude and more than 150 times more effective than the tetrapeptide CVIL and the methyl benzoate derivatives, respectively. The bivalent compounds 6 and 8 were shown to be competitive inhibitors, suggesting that the CVIL module anchors the whole molecule to the GGTase I active site and delivers the other module to the targeting protein surface. Thus, our module-assembly approach resulted in simultaneous multiple-site recognition, and as a consequence, synergetic inhibition of GGTase I activity, thereby providing a new approach in designing protein-surface-directed inhibitors for targeting protein-protein interactions.
Synthesis of novel dendrimers incorporating a dye into the core
Zhang, Jidong,Drugeon, Gérémy,L'hermite, Nathalie
, p. 3599 - 3601 (2007/10/03)
Dendrimers 1a and 1b, with six and nine terminal tert-butyloxycarbonyl (t-Boc) protected amine groups, respectively, have been prepared by an efficient divergent synthetic approach. These novel dendrimers contain a dye Red-1 incorporated into the core, which adds to them, in addition to their physicochemical properties proper to dendrimers, an additional one that is the visibility perceptible to human eyes. This new property was particularly interesting in relation to our research of new carriers for active entities and/or antibodies.
Convergent synthesis and diversity of amino acid based dendrimers
Brouwer, Arwin J.,Mulders, Suzanne J. E.,Liskamp, Rob M. J.
, p. 1903 - 1915 (2007/10/03)
The synthesis of amino acid based dendrimers 25 (fifth generation, 32 endgroups), 30 (fourth generation, 81 endgroups), chiral dendrimer 23 (third generation, 8 endgroups) as well as core-modified dendrimers 34 and 38 by the convergent method is described. The amino acid building blocks are derived from hydroxybenzoic acid derivatives and amino alcohol derivatives, and access to a considerable molecular diversity of these novel dendrimers can be achieved, The synthesis can be carried out on a relatively large scale, and this easy access of the dendrimers may lead to many potential applications.
Molecular diversity of novel amino acid based dendrimers
Mulders, Suzanne J. E.,Brouwer, Arwin J.,Liskamp, Rob M. J.
, p. 3085 - 3088 (2007/10/03)
We have expanded the recently introduced methodology for the preparation of a novel amino acid based dendrimer in order to be able to synthesize a diversity of dendrimers. For this purpose different hydroxybenzoic acids and amino alcohols were used to prepare the required monomers, necessary for construction of the respective dendrimers.
